Selection Flashcards
What are the evolutionary problems the brain is trying to solve?
Survival and Reproduction
Specific functional system
one whose effects can be traced to a distinct location.
Example of a system with a specific function
The superior colliculus: Visual information is received from the retina, and processed by a somatotopic map, which directly influences eye movement
Generic function system
structures with repeating microarchitecture that process information from regions that perform widely different functions. All systems with a general function consist of reciprocal connects (re-entrant loops) with other regions.
Example of a system with a general function
the cerebellum
- has re-entrant loops with sensorimotor, cognitive, and motivational structures which allow the calibration and refinement of movement.
- It also possesses a repeated microarchitecture whereby the basic structural organisation is uniform across the cerebellum, despite having differing input/outputs.
What are two broad generic functions provided by the basal ganglia
- selection of the most appropriate movement, sensation, idea, emotion, etc… in a given situation based on previous experience
- reinforcement learning, whereby strategies are learnt that maximise the chance of a successful outcome in a given situation
How is the architecture of the basal ganglia relevant to its different functions?
The basal ganglia is functionally separated:
- Medial/Anterior = Limbic (NA/Caudate)
- Central = Associative (central striatum)
- Lateral/Posterior = Sensorimotor (putamen)
What are the major cell types/compositions within the striatum?
- 97% MSNs (medium spiny neurons): only cell type that projects out of the striatum.
- > 1% Cholinergic interneurons: receive thalamic and some cortical inputs and have a great influence on the function of the basal ganglia
- GABAergic interneurons
- VTA/SNpc dopaminergic neurons
What do the functional regions of the BG differ in?
o External inputs (cortex, limbic system, brainstem)
o Input functions (motivation, mood, cognition, sensorimotor)
Why is a brain area tasked with selection so important?
Our brain needs to address competing motivations (food, escape, fluid balance, pleasure) with the single set of muscles. Having a region specialised for selection allows relative importance of each motivation in order to determine which actions are executed.
Describe the disinhibitory loop of the BG
- The cortex has excitatory connections onto the MSNs of the striatum.
- MSNs have inhibitory projections onto SNpr neurons.
- The SNpr neurons tonically inhibit the thalamus.
- The thalamus has excitatory connections with the cortex.
A phasic excitatory burst from the cortex results in increased inhibition of SNpr neurons by increased MSN activity, which disinhibits the thalamus, allowing it to excite the cortex.
Mutual inhibition
The increased stimulation of a MSN by the cortex results in inhibition of nearby MSNs, to allow selection of an output channel.
Reinforcement learning
Reinforcement learning describes how actions that maximise the likelihood of a successful outcome are likely to be selected for.
Describe two targets where reinforcement can bias selection
- Cortical excitability
- Corticostriatal plasticity
What does dopamine signal?
Dopamine acts to signal the difference between and expected outcome and the actual outcome.
Describe an experiment to test the two modes of dopamine release on corticostriatal plasticity.
Experiment
Set up: Obtain an ex vivo slice from the thalamus/cortex that contains the desired circuitry
+ Insert stimulating electrode into the cortex and dopaminergic cells, as well as recording electrode on the MSNs
1. Stimulate the cortex on its own to obtain the baseline post-synaptic potential in MSNs
2. Co-stimulate dopamine cells and glutaminergic cortical cells
(Do this tonically/phasically to represent the absence/presence of a reward)
3. Stimulate the cortex on its own to determine if post-synaptic potential has increased/decreased
What is the evidence that dopamine release reinforces actions?
Intracranial self-stimulation involves the insertion of a stimulating electrode into the substantia nigra of a rat. The stimulation can be activated by a lever press. Rats will press the lever until exhaustion/death, indicating that the lever press action has been reinforced (to a pathological degree)
What is the evidence that dopamine release mediates corticostriatal plasticity?
Co-stimulation of cortical glutaminergic and dopaminergic inputs onto MSNs results in an increased post-synaptic potential after co-stimulation comparative to before. The absence of phasic dopamine during cortical stimulation results in a decreased post-synaptic potential, indicative of long term depression.
Corticostriatal potentiation requires D1 receptors, as potentiation does not occur in presence of a D1 antagonist.
Greater corticostriatal plasticity correlated to faster learning.
Corticostriatal plasticity is initiated when, and only when, the stimulus meriting phasic dopamine occurs within 2 seconds of cortical activation.
Sub-cellular mechanism of corticostriatal LTP
Glutamate is released from the thalamus/cortex and binds to AMPA receptors on MSNs
- AMPA receptor activation leads to cation influx and depolarisation
- Depolarisation repels the Mg2+ in NMDA channels
- NMDA activation allows calcium influx
Dopamine is released, and binds to D1 receptors (facilitated by TAN pause)
- Activation of Gas, causing increase in cAMP
Downstream results
- AMPA phosphorylation, which increases their efficacy, as well as changes in gene transcription and membrane expression
Subcellular mechanism of LTD
Glutamate binds to AMPA receptors
- Cation influx
- Depolarisation
Activation of L-type voltage-dependent calcium channels
- TAN pause required, as ACh binds mAChR which inhibits L-type VGCC
- Calcium influx (+ lack of cAMP)
Endocannabinoid production
- endocannabinoid diffuses out and binds to pre-synaptic membrane
- decreases glutamate release
What is corticostriatal LTP?
A POST-SYNAPTIC process enabled by phasic DA action on D2 & glutamate release
What is corticostriatal LTD?
A PRE-SYNAPTIC process enabled by the presence of tonic dopamine and action on D2
Give 4 pieces of evidence that associate dopamine with reward
- Dopamine cells exhibit phasic bursts in response to rewarding or reward-predicting stimuli
- Dopamine release in response to rewarding stimuli has been released in the striatum through electrochemical recording with carbon fibre electrodes
- Stimulation of dopamine pathways is rewarding
(ICSS: Stimulating electrodes reinforced behaviour more the closer they were to dopamine cells) - D1 receptor antagonists reduce the effectiveness of rewards
(Shifts dose-response curve of reward-related lever-press behaviour to the right)
Electrochemistry (DA)
Implantation of a carbon fibre electrode containing an electric potential. When implanted in dopamine cells the electrical potential oxidises dopamine, allowing measurement of current.
Goal directed behaviour
behaviour based on previous experience with action-outcome associations, and involves planning
- Therefore is associated with the limbic medial/anterior basal ganglia loops
- SNpc/VTA -> Nucleus accumbens -> cortex
Habitual behaviour
behaviour directed by stimulus-response associations
- Therefore is a sensorimotor process controlled by the lateral/posterior basal ganglia loops
- SNpc/VTA -> striatum -> cortex
What is the progression of cell death in parkinsons? + Implication
In PD the substantia nigra typically dies of unilaterally, beginning in the lateral posterior regions.
- This explains the prevalence of motor symptoms, as the lateral posterior region of the basal ganglia (putamen) is involved in motor selection.
- This results in a loss of habitual behaviour, causing individuals to rely on goal-directed behaviour (i.e. they have to be consciously focusing on everything) which is mentally draining
List three general ways that acetylcholine (ACh) can alter striatal function
- Directly affecting the excitability of MSNs/SPNs
- Affecting dopamine release
- Altering the induction of corticostriatal plasticity
What is the morphology of cholinergic interneurons?
These neurons are large, and have smooth dendritic spines.
- Because they lack the isolated neurochemical reception site that these spines create, all input into cholinergic neurons affects adjacent inputs.
What is the firing pattern of cholinergic interneurons?
Cholinergic interneurons are tonically active, and fire at a frequency of 6-10Hz. Hence why they have been referred to as TANS.
How do cholinergic interneurons respond to salient stimuli?
the TANs exhibit a pause response which may be preceded by a transient increase in firing. This response is a temporary interruption in firing that lasts around 200ms.
This occurs synchronously in TANs throughout the striatum, and results in a widespread decrease in acetylcholine, as any residual ACh is rapidly degraded by the fast action of acetylcholine esterase (AChE)
How do striatal dopamine inputs respond to salient stimuli?
Dopamine cells also exhibit a response to salient stimuli, except this response is only elicited by reward-related salient stimuli, and is characterised by a phasic release of dopamine.
Differences between TAN/DA nR response
TANs and dopaminergic neurons differ in their expectancy effect; the lack of an expected reward decreases dopaminergic activity and does not affect TANs. But an unexpected reward increases the response in both populations.
Contextual modulating factors also differ
- reward-related dopaminergic firing increases when there is greater desire, and TANs show modulation of response by behavioural context, movement, and stimuli location.
- TANs can also respond to aversive stimuli (respond to any salient stimuli), whilst dopamine neurons do not (only respond to reward-related salient stimuli).
What trait is similar in the response of TANs/DA nRs to a salient stimuli?
Both neuronal populations adapt over time to preferentially respond to the conditioned stimulus (and not the actual reward) and this response dampens with excessive repetition.
What are the side effects of dopamine-based medication for PD?
L-DOPA: dyskinesias due to random dopamine fluctuations causing inappropriate reinforcement of motor programmes
D2 agonists: increased addictive behaviour (kleptomania, gay sex, gambling) due to increased likelihood of D1 activation.
Potential mechanism for drug addiction as a disorder of selection?
Most forms of drug addiction involve the use of dopamine increasing substances, which result in inappropriate LTP within the nucleus accumbens. This causes the formation of strong associations between drug use and related stimuli with reward.
Potential mechanism for OCD as a disorder of selection?
Can be thought of as excessive activity in certain ‘behavioural channels’ causing particular stimuli or actions to become over-represented as inputs to the striatum. This increases the likelihood these stimuli/actions will become selected in the future.
Treated with dopamine antagonists (thought to dampen overactive input) or dopamine agonists (thought to increase other inputs)
Potential mechanism for schizophrenia/psychosis as a disorder of selection?
Associated with a hyperdopaminergic state (especially during psychosis) which may be responsible to inappropriate LTP causing abnormal associations between ideas and thoughts.
Schizophrenia
characterised by disordered thoughts, hallucinations, and delusions
OCD
OCD is the presence of Obsessions: recurrent, intrusive, undesired thoughts
and/or
Compulsions: uncontrollable repetitive acts
Drug addiction
a chronic, relapsing disorder characterised by compulsive drug seeking and use despite adverse consequences
What are the 8 functional interactions of dopamine and acetylcholine
- Parkinson’s disease, which is characterised by dopamine loss, also involves an increase in cholinergic activity.
- treatment with anticholinergics has been shown to improve symptoms in humans
- optogenetic silencing of TANs improves PD symptoms in mice mouse - Dopamine acts on thalamo-cholinergic synapses to strengthen them
- Lack of dopamine results in loss of previously established TAN pause responses
- Phasic dopamine inhibits TANs through D2
- the TAN pause amplifies phasic dopamine release by releasing them from nAChR desensitisation
- TAN pause acts as a temporal window for phasic dopamine to alter synapses for reinforcement
- LTP - TAN pause amplifies phasic DA
- LTD - tonic DA inhibits TANs via D2 to release L-type voltage gated calcium channels from muscarinic ACh mediated inhibition
